Letrozole, 4,4′-(1H-1,2,4-triazol-1-ylmethylene)bisbenzonitrile, which has the chemical structure
is an aromatase inhibitor, used for the first line treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy, and has been approved in the United States for postmenopausal women who have finished five years of treatment with Tamoxifen. As with other aromatase inhibitors, letrozole inhibits the action of the enzyme aromatase in the formation of estrogen.
U.S. Pat. No. 4,978,672 (“'672 patent”) describes the synthesis of letrozole by reacting 4-(bromomethyl)benzonitrile I—Br
and 1H-1,2,4-triazole II
to provide 4-[1-(1,2,4-triazolyl)methyl]benzonitrile III,
which is then purified by column chromatography, and subsequently converted to letrozole by reaction with 4-fluoro-benzoacetonitrile V

According to International Publication No. WO 2004/076409 (“WO '409”), compound III is purified by column chromatography in the '672 patent before conversion to letrozole, because it is contaminated with 4-[1-(1,3,4-triazolyl)methyl]benzonitrile IV,
WO '409 discloses that compound III is contaminated with approximately 20 to 40% of compound IV. WO '409 further recites that when the reaction of compound III with compound V is performed without the removal of the impurity (compound IV), the impurity is converted into 4,4′-(1H-1,3,4-triazol-1-ylmethylene)bisbenzonitrile VI,
also known as letrozole related compound A, which is restricted to 0.3% by the USP Official Monographs, 28, 1112-1113 (2005). This need for purification of compound III makes the process of the '672 patent tedious, as well as unattractive commercially.
WO '409 describes an alternative process, which avoids the formation of compound IV by using an amino substituted triazole. However, this process requires an additional step to remove the amino substituent, which may involve the formation of dangerous diazo intermediates. Thus, the process is also undesirable for use on a commercial scale.
U.S. Pat. No. 5,352,795 discloses that, when the reaction of compound III with compound V is conducted according to the process disclosed in that patent, a competing side-reaction occurs between 4-fluorobenzonitrile V, 4-tolunitrile, an impurity of the 4-(bromomethyl)benzonitrile starting material for the preparation of letrozole, and potassium t-butoxide, leading to the formation of significant amounts the “tris” impurity VII
that contaminates letrozole. Moreover, the side-reaction consumes a portion of the 4-fluorobenzonitrile V reactant, requiring an excess of that reactant to complete the desired condensation of the reactant with the intermediate III.
U.S. Pat. No. 5,280,035 describes a process for preparing compound III by the reaction of 1,2,4-triazole with sodium hydride in dimethylformamide, followed by addition of 4-(bromomethyl)benzonitrile at 5° C. To obtain the desired purity, compound III must be isolated by column chromatography.
U.S. Patent Application Publication No. 2005/0209294 also describes a process for preparing compound III by reaction of 1,2,4-triazole sodium salt with 4-(bromomethyl)benzonitrile in dimethylformamide. Compound II is isolated by crystallization with greater than 96% selectivity, and, thus, contains a high percentage of compound IV. In example I of U.S. Patent Application Publication No. 2005/0209294, the extraction was done without distilling away the dimethylformamide, and adding dichloromethane and water. The organic phase gives a less efficient separation of the 2 isomers, such that, after precipitation, the ratio is 96/4.
Therefore, a need exists for a process that minimizes or substantially eliminates the formation of the impurities, compound IV and compound VII, in the synthesis of the intermediate III, and of letrozole, respectively.